Effectiveness and Cost of Weekly Recombinant Tissue Plasminogen Activator Hemodialysis Catheter Locking Solution.

BACKGROUND AND OBJECTIVES: Evidence to guide hemodialysis catheter locking solutions is limited. We aimed to assess effectiveness and cost of recombinant tissue plasminogen activator (rt-PA) once per week as a locking solution, compared with thrice weekly citrate or heparin, in patients at high risk of complications. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used a prospective design and pre-post comparison in three sites across Canada. Pre-post comparisons were conducted using multilevel mixed effects regression models accounting for cluster with site and potential enrollment of patients more than once. In the pre period, catheter malfunction was managed as per site-specific standard of care. The intervention in the post period was once weekly rt-PA as a locking solution (with citrate or heparin used for other sessions). The primary outcome was rate of rt-PA use for treatment of catheter malfunction. Secondary outcomes included rates of bacteremia, management of catheter malfunction, and cost. RESULTS: There were 374 patients (mean age 68 years; 52% men) corresponding to 506 enrollments. Mean length of enrollment was 200 days (SD 119) in the pre period and 187 days (SD 101) in the post period. There was a significant decline in rate of rt-PA use for treatment of catheter malfunction in the post compared with pre period (adjusted incidence rate ratio, 0.39; 95% confidence interval, 0.30 to 0.52); however, there was no difference in the rate of bacteremia, or catheter stripping or removal/replacement. The increase in mean total health care cost in the post period was CAD$962 per enrollment, largely related to costs of rt-PA as a locking solution. CONCLUSIONS: Once weekly rt-PA as a catheter locking solution was associated with a reduction in rt-PA use for treatment of catheter malfunction. Our results showing a reduction in rescue rt-PA use are consistent with a prior randomized trial, although we did not observe a reduction in bacteremia or catheter stripping/removal and did observe an increased incremental cost of this strategy primarily accounted for by the cost of the rt-PA.

Streptokinase and enoxaparin as an alternative to fibrin-specific lytic-based regimens: an ExTRACT-TIMI 25 analysis.

BACKGROUND: Enoxaparin was superior to unfractionated heparin (UFH), regardless of fibrinolytic agent in ST-elevation myocardial infarction (STEMI) patients receiving fibrinolytic therapy in ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment - Thrombolysis in Myocardial Infarction 25) trial. OBJECTIVE: This post hoc analysis compared outcomes with streptokinase plus enoxaparin to the standard regimen of fibrin-specific lytic (FSL) plus UFH and to the newer combination of FSL plus enoxaparin. METHODS: In ExTRACT-TIMI 25, STEMI patients received either streptokinase or a FSL (alteplase, reteplase or tenecteplase) at the physician's discretion and were randomized to enoxaparin or UFH, stratified by fibrinolytic type. Thirty-day outcomes were adjusted for baseline characteristics, region, in-hospital percutaneous coronary intervention (PCI) and a propensity score for the choice of lytic. RESULTS: The primary trial endpoint of 30-day death/myocardial infarction (MI) occurred in fewer patients in the streptokinase-enoxaparin cohort (n = 2083) compared with FSL-UFH (n = 8141) [10.2% vs 12.0%, adjusted odds ratio [OR(adj)] 0.76; 95% CI 0.62, 0.93; p = 0.008]. Major bleeding was significantly increased with streptokinase-enoxaparin compared with FSL-UFH (OR(adj) 2.74; 95% CI 1.81; 4.14; p < 0.001) but intracranial haemorrhage (ICH) was similar (OR(adj) 0.90; 95% CI 0.40, 2.01; p = 0.79). Net clinical outcomes, defined as either death/MI/major bleeding or as death/MI/ICH tended to favour streptokinase-enoxaparin compared with FSL-UFH (OR(adj) 0.88; 95% CI 0.73, 1.06; p = 0.17; and OR(adj) 0.77; 95% CI 0.63, 0.93; p = 0.008, respectively). Patients receiving FSL-enoxaparin (n = 8142) and streptokinase-enoxaparin therapies experienced similar adjusted rates of the primary endpoint (OR(adj) 1.08; 95% CI 0.87, 1.32; p = 0.49) and net clinical outcomes. CONCLUSIONS: Our results suggest that fibrinolytic therapy with the combination of streptokinase and the potent anticoagulant agent enoxaparin resulted in similar adjusted outcomes compared with more costly regimens utilizing a FSL.

Cost-effectiveness of thrombolytics: a simplified model.

OBJECTIVE OF THE STUDY: To construct a simple model for an internal, retrospective cost-effectiveness analysis and to calculate the incremental cost-effectiveness of tissue plasminogen activator (TPA) over streptokinase (SK) in Turkey. SETTING: Kosuyolu Heart, Education and Research Hospital, Istanbul, Turkey. METHOD: Among patients who were hospitalized for treatment of acute myocardial infarction (AMI), 196 were randomly selected. One-year mortality rates according to the treatment groups (TPA, SK, other) were determined. Among surviving patients, 28 from TPA and another 28 from SK group were randomly selected for the pharmacoeconomic analysis. Patient treatment data were taken from medical records while data regarding to costs were taken from hospital bills. MAIN OUTCOME MEASURES: Incremental cost-effectiveness ratio (ICER). The cost part of the ratio was considered as 'the overall-costs', while the effectiveness part was considered as 'lives saved' per treatment group. RESULTS: With an increased one-year survival rate of 2.37% and an increased cost of euro 1120.8 ($1165.6) per patient in the TPA group, the ICER for the use of TPA instead of SK was euro 47,289 ($49,180.6) per life saved. CONCLUSION: This model can be a guide for similar analyses. The results of our study (the incremental cost-effectiveness of TPA over SK) will be informative for the decision-makers in Turkey, by whom the medical benefit for money spent would be assessed and judged. We believe that our results make a contribution to similar studies in the literature.

Economic evaluation of treatment strategies for patients suffering acute myocardial infarction in Greece.

INTRODUCTION: Acute myocardial infarction (AMI) is one of the leading causes of death in Greece and elsewhere. The objective of this paper was to conduct an economic evaluation of three alternative treatment options, alteplase, reteplase, and tenecteplase, in different groups of patients. METHODS: A systematic review of the literature was undertaken to identify studies evaluating the three treatments considered. Data from selected trials were extracted and applied to a decision analytic model, which has a time horizon extending to the end of a patient's life. The health outcomes included in the analysis contain all major health events that may occur after an AMI. Total treatment cost comprises the cost of initial treatment, the cost associated with hospitalisations due to AMI and events such as stroke, reinfarction, etc., and the lifetime costs of patients surviving. The model allows for different patient sub-groups. Simulation was used to test the robustness of the findings. RESULTS: For the baseline group, there was no major difference between the three treatments, in terms of treatment cost and survival. Specifically, lifetime cost per patient was around Euro 18,950 (range Euro 18,947 - Euro 18,990) and overall survival was around 8.4 years (range 8.359 - 8.472). Nonetheless, for patients above the age of 75 and for patients starting treatment 4 hours after symptom onset, tenecteplase was more cost-effective compared to the other two treatments. Its incremental cost effectiveness ratio was Euro 2,205 in the former group and Euro 868 in the latter and these results reached high levels of significance. CONCLUSION: Despite its higher price, in the setting of the Greek National Health Service tenecteplase is a cost-effective treatment for AMI patients, comparable to alteplase and reteplase, and it should also be included in the positive drug list along with the other two drugs. Simple price comparison of alternative treatments is not the best option for supporting decisions on pricing and reimbursement of new therapies.

Comparison of urokinase, alteplase, and reteplase for catheter-directed thrombolysis of deep venous thrombosis.

PURPOSE: To compare the efficacy, safety, and costs associated with catheter-directed thrombolysis with urokinase (UK) and the recombinant agents alteplase (tissue plasminogen activator [TPA]) and reteplase (recombinant plasminogen activator [RPA]) in the treatment of symptomatic deep vein thrombosis (DVT). MATERIALS AND METHODS: The authors conducted a retrospective analysis on 74 patients (82 limbs) who underwent treatment for DVT. Thrombosed extremities were treated with either urokinase with therapeutic heparin dosing (UK group; 38 limbs), alteplase with subtherapeutic heparin dosing (TPA group; 32 limbs), or reteplase with subtherapeutic heparin dosing (RPA group; 12 limbs). Infusion times, dosages, drug costs, success rates, and complications were compared among the groups. RESULTS: Gender, age, disease location, duration of symptoms, and use of additional interventional therapies did not differ statistically among the three cohorts. Median hourly infused doses, total doses, infusion times, drug costs, and success rates per limb were: UK, 11.3 (10(4)) U/hour, 4.361 million U, 40.6 hours, US dollars 6577, 97.4%; TPA, 0.57 mg/hour, 21.6 mg, 30.8 hours, US dollars 488, 96.9%; RPA, 0.74 U/hour, 21.4 U, 24.3 hours, US dollars 1787, 100.0%. Major and overall complication rates were: UK, 5.3% and 10.5%; TPA, 3.1% and 12.5%; RPA, 8.3% and 16.7%. Infusion times, success rates, and complications were not statistically different among the three groups. Alteplase and reteplase were significantly less expensive than urokinase (P <.001 and P <.01, respectively). CONCLUSION: Catheter-directed thrombolysis for the treatment of DVT is safe and effective, regardless of the agent used. However, the new recombinant agents are significantly less expensive than urokinase.

The safety, efficacy, and pharmacoeconomics of low-dose alteplase compared with urokinase for catheter-directed thrombolysis of arterial and venous occlusions.

PURPOSE: The purpose of this study was to compare the efficacy, complications, and costs associated with low-dose (<2 mg/h) alteplase (tissue plasminogen activator [t-PA]) versus urokinase for the catheter-directed treatment of acute peripheral arterial occlusive disease (PAO) and deep vein thrombosis (DVT). MATERIALS AND METHODS: A retrospective review was performed during sequential time periods on two groups with involved extremities treated with either t-PA with subtherapeutic heparin (TPA group) or urokinase with full heparin (UK group) at a single center. Treatment group characteristics, success rates, complications, dosages, infusion time, and costs were compared. RESULTS: Eighty-nine patients with 93 involved limbs underwent treatment (54 with DVT, 39 with PAO). The treatment groups were statistically identical (TPA: 45 limbs; 24 with DVT, 53.3%; 21 with PAO, 46.7%; UK: 48 limbs; 30 with DVT, 62.5%; 18 with PAO, 37.5%). The overall average hourly infused dose, total dose, infusion time, success rates, and cost of thrombolytic agent were as follows (+/- standard deviation): TPA, 0.86 +/- 0.50 mg/h, 21.2 +/- 15.1 mg, 24.6 +/- 11.2 hours, 89.4%, $466 +/- $331; and UK, 13.5 +/- 5.6 (10(4)) U/h, 4.485 +/- 2.394 million U, 33.3 +/- 13.3 hours, 85.7%, $6871 +/- $3667, respectively. Major and minor complication rates were: TPA, 2.2% and 8.9%; and UK, 2.1% and 10.4%, respectively. No statistical differences in success rates or complications were observed; however, t-PA was significantly (P <.05) less expensive and faster than urokinase. CONCLUSION: Low-dose t-PA combined with subtherapeutic heparin is equally efficacious and safe compared with urokinase. Infusions with t-PA were significantly shorter and less expensive than those with urokinase.

Use of urokinase in childhood pleural empyema.

Urokinase is an enzyme with a fibrinolytic effect that facilitates pleural empyema drainage through a chest tube. The aim of this study was to assess the risk of pneumothorax, the need for pleural debridement surgery, the persistence of fever, and the number of days in hospital in a group of children with parapneumonic pleural empyema treated with urokinase. This was an uncontrolled retrospective study on children suffering from parapneumonic empyema. Data collected on 17 children treated with urokinase were compared with 11 children treated prior to the advent of urokinase (the "historic" group). The urokinase was instilled in the pleural cavity over a period ranging from 2-8 days, amounting to a median total dose per kilogram of body weight of 18,556 IU (range, 7,105-40,299). Surgical treatment of the empyema involved drainage tube placement and/or debridement of the pleural cavity. Three children developed pneumothorax during their hospital stay, and one more case occurred 6 months after the child had recovered from his empyema; there were 3 cases of pneumothorax during the acute phase in the "historic" group (P = 0.54). Five children in the urokinase group were debrided and 12 were only drained, as opposed to 9 and 2, respectively, in the "historic" group (P = 0.02). The overall hospital stay was 17 days for the urokinase group, and 24 for the "historic" group (P = 0.02). No bleeding or other major complications were reported in the group treated with urokinase. In conclusion, urokinase treatment does not carry a risk of pneumothorax, while it does reduce hospital stay and the need for pleural debridement.

Stability and sterility of recombinant tissue plasminogen activator at -30 degrees C.

We assessed whether frozen recombinant tissue plasminogen activator (rt-PA) remains stable and sterile for up to 22 weeks at -30 degrees C. Our findings confirm that rt-PA is a cost-effective alternative to urokinase for restoring patency to occluded central venous catheters.

Dynamically allocating treatment when the cost of goods is high and drug supply is limited.

Large-scale production of proteins by cell culture and subsequent purification for use in novel medical therapies is a slow and complex process. During the early phases of development of manufacturing processes, contamination and replication errors cause entire batches of material to be wasted. As a result, the cost of goods for large-molecule therapies in early clinical development can be significant, and the supply limited. When designing clinical trials to test expensive biological compounds with limited supply, sponsoring companies want to minimize the waste of drug, that is, to maintain small inventories of drug at the investigational hospitals. We must, however, weigh the benefits of smaller inventories against the costs of increased numbers of shipments to resupply when rapid enrollment causes shortages of drug. A well-planned randomization scheme may be able to balance these objectives. This paper demonstrates how a dynamic randomization algorithm can be used to maintain smaller drug inventory at hospitals than a typical permuted block randomization list plan, and how well it automatically restores balance when the shortage of drug causes assignment of alternate treatments.

Dialysis graft declotting with very low dose urokinase: is it feasible to use "less and wait?".

PURPOSE: "Lyse and wait" dialysis graft declotting is simple and effective, but the minimum necessary dose of urokinase is unknown. The efficacy of the technique with very low dose urokinase is evaluated. MATERIALS AND METHODS: Twenty-one grafts in 17 patients were declotted with use of the lyse and wait technique, but with 5,000-15,000 U of urokinase initially. Graft angiography was performed when an interventional suite was available. Declotting was completed in the manner chosen by the individual operator. Angiograms, interventional radiology records, and dialysis records were reviewed. RESULTS: Technical and clinical success were achieved in 95% of cases. Mean initial urokinase dose was 6,667 U. Initial angiography was performed at a mean 86 minutes. Two cases required second 5,000-U boluses to achieve complete graft thrombolysis. In all other cases, complete or near complete graft thrombolysis was observed with the initial very low dose. No bleeding, arterial embolic, or pulmonary embolic complications were observed. CONCLUSIONS: Doses of urokinase as low as 5,000 U are effective for lyse and wait declotting. A substantial reduction in drug costs can be expected with the "less and wait" modification. Bleeding risk may also be reduced.

Effects of stroke on medical resource use and costs in acute myocardial infarction. GUSTO I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries Study.

BACKGROUND: Stroke occurs concurrently with myocardial infarction (MI) in approximately 30 000 US patients each year. This number is expected to rise with the increasing use of thrombolytic therapy for MI. However, no data exist for the economic effect of stroke in the setting of acute MI (AMI). The purpose of this prospective study was to assess the effect of stroke on medical resource use and costs in AMI patients in the United States. METHODS AND RESULTS: Medical resource use and cost data were prospectively collected for 2566 randomly selected US GUSTO I patients (from 23 105 patients) and for the 321 US GUSTO I patients who developed non-bypass surgery-related stroke during the baseline hospitalization. Follow-up was for 1 year. All costs are expressed in 1993 US dollars. During the baseline hospitalization, stroke was associated with a reduction in cardiac procedure rates and an increase in length of stay, despite a hospital mortality rate of 37%. Together with stroke-related procedural costs of $2220 per patient, the baseline medical costs increased by 44% ($29 242 versus $20 301, P<0.0001). Follow-up medical costs were substantially higher for stroke survivors ($22 400 versus $5282, P<0.0001), dominated by the cost of institutional care. The main determinant for institutional care was discharge disability status. The cumulative 1-year medical costs for stroke patients were $15 092 higher than for no-stroke patients. Hemorrhagic stroke patients had a much higher hospital mortality rate than non-hemorrhagic stroke patients (53% versus 15%, P<0.001), which was associated with approximately $7200 lower mean baseline hospitalization cost. At discharge, hemorrhagic stroke patients were more likely to be disabled (68% versus 46%, P=0.002). CONCLUSIONS: In this first large prospective economic study of stroke in AMI patients, we found that strokes were associated with a 60% ($15 092) increase in cumulative 1-year medical costs. Baseline hospitalization costs were 44% higher because of longer mean lengths of stay. Stroke type was a key determinant of baseline cost. Follow-up costs were more than quadrupled for stroke survivors because of the need for institutional care. Disability level was the main determinant of institutional care and thus of follow-up costs.

Urokinase efficacy in the restoration of hemodialysis catheter function.

Thrombus formation is a common cause of hemodialysis catheter malfunction. When thrombus or fibrin sheath restrict the flow of blood through one or both lumens, the catheter may need to be replaced. A less invasive, potentially lower cost option may be the instillation of low dose urokinase to degrade fibrin and restore catheter function. This study examines the efficacy of urokinase in improving blood flow and maintaining catheter patency. In a one-year period, urokinase was utilized in 25 dual lumen hemodialysis catheters (20 temporary, five permanent) in 22 patients. Blood flow and arterial and venous pressures were monitored before and after instillation. Urokinase administration successfully restored function in 20 catheters (80%). Paired t-tests demonstrated a significant improvement in blood flow and arterial pressure (p < 0.01) following urokinase. Catheter patency was extended for a mean of 18.0 days (range 0-90 days). The cost effectiveness of urokinase was evaluated in terms of direct costs, such as the cost of urokinase or materials to replace catheters, and indirect costs such as nursing and physician time and delays in dialysis scheduling. The results of this study suggest that judicious use of urokinase is a cost-effective, non-invasive method of restoring blood flow and extending patency in hemodialysis catheters.

Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke. NINDS rt-PA Stroke Study Group.

Tissue plasminogen activator (tPA) has been shown to improve 3-month outcome in stroke patients treated within 3 hours of symptom onset. The costs associated with this new treatment will be a factor in determining the extent of its utilization. Data from the NINDS rt-PA Stroke Trial and the medical literature were used to estimate the health and economic outcomes associated with using tPA in acute stroke patients. A Markov model was developed to estimate the costs per 1,000 patients eligible for treatment with tPA compared with the costs per 1,000 untreated patients. One-way and multiway sensitivity analyses (using Monte Carlo simulation) were performed to estimate the overall uncertainty of the model results. In the NINDS rt-PA Stroke Trial, the average length of stay was significantly shorter in tPA-treated patients than in placebo-treated patients (10.9 versus 12.4 days; p = 0.02) and more tPA patients were discharged to home than to inpatient rehabilitation or a nursing home (48% versus 36%; p = 0.002). The Markov model estimated an increase in hospitalization costs of $1.7 million and a decrease in rehabilitation costs of $1.4 million and nursing home cost of $4.8 million per 1,000 eligible treated patients for a health care system that includes acute through long-term care facilities. Multiway sensitivity analysis revealed a greater than 90% probability of cost savings. The estimated impact on long-term health outcomes was 564 (3 to 850) quality-adjusted life-years saved over 30 years of the model per 1,000 patients. Treating acute ischemic stroke patients with tPA within 3 hours of symptom onset improves functional outcome at 3 months and is likely to result in a net cost savings to the health care system.

Incremental cost-effectiveness ratio of alteplase in patients with acute myocardial infarction in the French setting.

On the basis of data collected from general hospital centres in France on 704 patients initially presenting with acute myocardial infarction, the mean 1-year cost of treatment was calculated to be 52,160 French francs (F) per patient (1994 values). This was independent of whether the patient received thrombolysis, and included all costs associated with initial hospitalisation including a stay in intensive care, cardiology or medical units, as well as rehospitalisations, revascularisation procedures and any drugs prescribed. When only those patients who survived the initial hospitalisation were considered, the mean cost of treatment was F58,184 per patient. Among patients who received thrombolysis during their initial hospitalisation, the respective mean 1-year costs were F74,684 per patient for those treated with alteplase and F64,866 per patient for those treated with streptokinase (p = 0.09). This nonsignificant difference can be explained by the higher cost of alteplase relative to that of streptokinase, the lower mortality rate associated with alteplase during the initial hospitalisation period (9.2% versus 10.6%) and the difference in the percentage of additional revascularisations required in the 2 treatment groups (32.8% versus 42.3%). Combining the pharmacoeconomic data collected in the French general hospital setting with incremental patient survival data stemming from the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial showed that the incremental cost-effectiveness ratio of alteplase versus streptokinase amounted to F70128 per life-year saved for the total group, and F52035 per life-year saved for those patients who survived the initial period of hospitalisation.

Treatment of embolic stroke as a medical emergency. Implications in a managed care environment.

Encouraging innovations should be a concern of the providers/gatekeepers of health-care if lower health-care costs are to become a reality. Controlled prices and improper incentives will dramatically slow innovation in American medicine. For the vertically integrated health-care system providing capitated coverage, the aggressive treatment of stroke is a sound financial decision.